Oral Anticoagulant Therapy Benedict R Lucchesi M D

Oral Anticoagulant Therapy Benedict R. Lucchesi, M. D. , Ph. D. Department of Pharmacology University of Michigan Medical School

O O WARFARIN SODIUM CH ONa CH 2 CO CH 3 O O DICUMAROL CH 2 OH OH

Warfarin: Mechanism of Action • Interferes with the cyclic interconversion of vitamin K and its 2, 3 epoxide (vitamin K epoxide) • Vitamin K is an essential cofactor for post-translational carboxylation of glutamate residues on the N-terminus regions of vitamin K-dependent proteins to gammacarboxy-glutamates • Descarboxyprothrombin is converted to prothrombin by carboxylation of glutamate residues to gammacarboxyglutamate

Warfarin - Mechanism of Action – By inhibiting vitamin K epoxide reductase and vitamin K reductase, warfarin leads to the accumulation of vitamin K epoxide in the liver and plasma and the depletion of reduced vitamin K (active form, KH 2) – Reduced vitamin K is necessary for carboxylation of glutamate residues – Decrease in KH 2 limits the gamma-carboxylation of vitamin K dependent coagulant proteins – Prothrombin (Factor II) – Factors VII, IX, X – Protein C and Protein S

How does gamma-carboxylation affect the vitamin K dependent proteins ? –gamma-carboxylation gives the proteins the ability to bind CALCIUM IONS –in the presence of calcium, the proteins undergo a conformational change –this allows them to bind to their respective cofactors on phospholipid surfaces

Warfarin - Pharmacokinetics Pharmacodynamics • Racemic mixture of two optical isomers • Absorbed rapidly from GI tract • Maximal plasma concentration in 90 min • Plasma t 1/2 of 36 to 42 hours • Circulates bound to plasma proteins • Administered orally

Warfarin - drug-drug interactions Prolong prothrombin time • Stereoselective inhibition of clearance of the Sisomer • Phenylbutazone • Metronidazole • Sulfinpyrazone • Trimethoprim-sulfamethoxazole • Disulfuram

Warfarin - drug-drug interactions Prolong prothrombin time • Change Warfarin Plasma Concentration – Stereoselective inhibition of clearance of the Risomer • Cimetidine • Omeprazole – Nonstereoselective inhibition of R and S isomers • Amiodarone

Warfarin - drug-drug interactions Prolong Prothrombin Time • Do Not Change Warfarin Plasma Concentration • Inhibits cyclic interconversion of vitamin K • 2 nd and 3 rd Generation of cephalosporins • Other Mechanisms • Clofibrate • Inhibits Blood Coagulation • Heparin • Increases metabolism of coagulation factors • Thyroxine

Warfarin - drug-drug interactions Prolong Prothrombin Time Effects on Warfarin Plasma Concentration are Unknown Evidence is strong: • Erythromycin • Anabolic steroids Evidence is lacking: • Ketoconazole; Fluconazole; Isoniazid • Piroxicam; Tamoxifen; Quinidine; Phenytoin

Warfarin - drug-drug interactions Inhibit Platelet Function- Do Not Change Warfarin Plasma Concentration • Aspirin • Ticlopidine • Clopidogrel • Moxalactam • Carbenicillin and high doses of other penicillins

Warfarin - drug-drug interactions Reduce Prothrombin Time • Change Warfarin Plasma Concentration • Cholestyramine (reduces absorption of Warfarin) • Increase metabolic clearance of warfarin • Barbiturates • Rifampin • Griseofulvin • Carbamazepine

Therapeutic Range for Oral Anticoagulant Therapy • Dose adjusted on the basis of laboratory tests • Most often used is the one-stage prothrombin time • PT is sensitive to: Factors II, VII, and X • Makes use of Ca++ plus thromboplastin added to patient’s citrated plasma - record time to clot THROMBOPLASTINS DIFFER IN SENSITIVITY TO THE REDUCTION OF VITAMIN K-DEPENDENT CLOTTING FACTORS

Warfarin results in altered hepatic synthesis of several vitamin K-dependent factors Factor Coagulant Anticoagulant T 1/2 Factor II Factor VII Factor IX Factor X yes yes no no 50 hrs 6 hrs 24 hrs 36 hrs _________________ Protein C no yes 8 hrs Protein S no yes 30 hrs Both Factor VII and Protein C have short T 1/2. The decrease in Factor VII activity is countered by the thrombogenic effect of decreased Protein C in the first 24 hours

Warfarin - Dosing Considerations • Onset of anticoagulant effect is delayed as existing clotting factors (II, VII, IX, X, Protein C and Protein S) must be cleared from the circulation. • Effect occurs within 24 hours as Factor VII (short t 1/2 = 6 -7 hrs) is reduced to a critical value. • Peak activity in about 72 - 96 hours - longer t 1/2 of Factors II, IX, X.

Warfarin - Dosing Considerations • Protein C has a short t 1/2 as does Factor VII • In the early phase of treatment (24 - 48 hrs) the relative reduction in the activity of protein C will enhance the prothrombotic action of Factor VII • Remember, Protein C exerts a negative feed-back on thrombin via Factor VIII and Factor V.

Warfarin - Pharmacokinetics • Only a small amount of the total circulating drug, 1 - 2% causes the pharmacologic effect. • Displacement of warfarin from albumin binding sites augments the plasma concentration of active drug and can increase the anticoagulant effect. • Half life of racemic warfarin ranges from 20 - 60 hours, reflecting the contribution of its dextro- and levo- isomers. • d- isomer has longer half-life. l - isomer is 5. 5 times more active. Each isomer is metabolized by different pathways. Levo metabolites appear in the bile, dextro-metabolites appear in the urine.

Warfarin - Clinical Uses • Oral anticoagulants are effective in the primary and secondary prevention of venous thromboembolism • Prevention of systemic embolism in patients with prosthetic heart valves or atrial fibrillation • Prevention of stroke, recurrent infarction, and death in patients with acute MI • INR of 2. 0 - 3. 0 (moderate-intensity regimen) is satisfactory for most situations

Warfarin - Adverse Effects • Bleeding is the main concern, risk depends on: –Intensity of therapy –Patient’s underlying disorder –Concomitant use of aspirin or antiplatelet drugs. –Patient’s age - risk > 65 yrs old, hx of stroke, hx of GI bleeding –Bleeding with an INR < 3, usually due to some occult cause, GI or renal lesion

Warfarin - Adverse Effects • Most important non-hemorrhagic effect is skin necrosis • Occurs on 3 rd to 8 th day of dosing • Due to excessive thrombosis of venules and capillaries in • subcutaneous fat May be associated with Protein C deficiency - initiation of warfarin therapy can induce a rapid decline in protein C because of its short half life (7 hours) resulting in a parodoxical syndrome of transient hypercoagulation and microthrombus formation beginning before effective anticoagulation is achieved.

Warfarin in pregnancy Crosses the placenta Produces characteristic embryopathy, CNS abnormalities, fetal bleeding • Embryopathy consists of: • nasal hypoplasia • stippled epiphyses • agenesis of corpus callosum • ventral midline dysplasia - optic atrophy

Management of Warfarin Overdose Excessive anticoagulant effect of warfarin can be reversed by: • stopping the drug • administering large doses of vitamin K 1 (5 to 10 mg; may need to repeat dose) • administering fresh-frozen plasma (10 -20 ml/kg) • • combined with vitamin K 1 administering factor IX concentrate Improvement in hemostasis does not occur for several hours - may require 24 hours.

Dosing Regimens for Anticoagulation • Warfarin (Oral Administration) –Day 1 - 15 mg –Day 2 - 10 mg –Day 3 - 10 mg –Maintenance dose is 5 to 7. 5 mg daily, but there is marked variation among patients –Prothrombin time changes little in first 24 hours with gradual prolongation by the third day.

Warfarin Anticoagulation Failure • Altered oral bioavailability – drug/food interaction within the GI tract • Variations in Vitamin K availabililty – dietary – altered GI flora • Drug/Drug Interactions – displacement from plasma albumin – altered hepatic metabolism (cytochrome p 450) • Hereditary Resistance – Rare disorder characterized by autosomal dominant inheritance. – Individuals may require up to 75 -80 mg of warfarin to achieve a therapeutic prothrombin time.